Nefazodone Hydrochloride
C25H32ClN5O2·HCl 506.47
3H-1,2,4-Triazol-3-one, 2-[3-[4-(3-chlorophenyl)-1-piperazinyl)]propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-, monohydrochloride;
1-[3-[4-(m-Chlorophenyl)-1-piperazinyl]propyl]-3-ethyl-4-(2-phenoxyethyl)-D2-1,2,4-triazolin-5-one monohydrochloride
[82752-99-6].
(ne faz' oh done hye'' droe klor' ide).
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C25H32ClN5O2·HCl 506.47
3H-1,2,4-Triazol-3-one, 2-[3-[4-(3-chlorophenyl)-1-piperazinyl)]propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-, monohydrochloride;
1-[3-[4-(m-Chlorophenyl)-1-piperazinyl]propyl]-3-ethyl-4-(2-phenoxyethyl)-D2-1,2,4-triazolin-5-one monohydrochloride
[82752-99-6].DEFINITION
Nefazodone Hydrochloride contains NLT 98.0% and NMT 102.0% of C25H32ClN5O2·HCl, calculated on the dried basis.
IDENTIFICATION
• B. Identification Tests—General, Chloride 
191
:
Meets the requirements
191:
Meets the requirements
Sample solution:
10 mg/mL in methanol
ASSAY
• Procedure
Sample solution:
800 mg of Nefazodone Hydrochloride in 50 mL of glacial acetic acid. Add 15 mL of 3% mercuric acetate in glacial acetic acid.
Titrimetric system
(See Titrimetry 541.)
541.)
Titrant:
0.1 N perchloric acid VS
Endpoint detection:
Potentiometric
Analysis
Titrate with 0.1 N perchloric acid VS, determining the endpoint potentiometrically. Carry out a blank titration.
Calculate the percentage of C25H32ClN5O2·HCl in the portion of Nefazodone Hydrochloride taken:
Result = ((V 
B) × N × F/W) × 100
B) × N × F/W) × 100| V | = | = sample titrant volume (mL) |
| B | = | = blank titrant volume (mL) |
| N | = | = titrant normality (mEq/mL) |
| F | = | = 506.5 (mg/mEq) |
| W | = | = sample weight (mg) |
Acceptance criteria:
98.0%–102.0% on the dried basis
IMPURITIES
Organic Impurities
• Procedure
Diluent:
Acetonitrile and water (1:1)
Solution A:
0.77 g/L of ammonium acetate in water.
Adjust with triethylamine to a pH of 7.10 ± 0.05, and degas.
Solution B:
Acetonitrile (degassed)
Mobile phase:
See the gradient table below.
| Time (min) |
Solution A (%) |
Solution B (%) |
|---|---|---|
| 0 | 50 | 50 |
| 10 | 45 | 55 |
| 16 | 35 | 65 |
| 25 | 35 | 65 |
| 26 | 50 | 50 |
| 35 | 50 | 50 |
Impurities stock solution:
0.1 mg/mL of USP Nefazodone Related Compound A RS and USP Nefazodone Related Compound B RS in Diluent
Standard stock solution:
0.1 mg/mL of USP Nefazodone Hydrochloride RS in Diluent
System suitability solution:
5 µg/mL each of USP Nefazodone Related Compound A RS and USP Nefazodone Related Compound B RS from the Impurities stock solution in the Standard stock solution
Standard solution:
1 µg/mL each of Nefazodone Hydrochloride, USP Nefazodone Related Compound A RS, and USP Nefazodone Related Compound B RS from the Standard stock solution and the Impurities stock solution in Diluent
Sample solution:
1 mg/mL of Nefazodone Hydrochloride in Diluent
Chromatographic system
Mode:
LC
Detector:
UV 250 nm
Column:
4.6-mm × 25-cm; 5-µm packing L1
Flow rate:
1.7 mL/min
Injection size:
10 µL
System suitability
Samples:
System suitability solution and Standard solution
Suitability requirements
Resolution:
NLT 4.0 between nefazodone related compound A and nefazodone hydrochloride; NLT 1.5 between nefazodone hydrochloride and nefazodone related compound B, System suitability solution
Relative standard deviation:
NMT 5.0% for nefazodone related compound A and nefazodone related compound B, Standard solution
Analysis
Samples:
Standard solution and Sample solution
Calculate the percentage of each nefazodone related compound in the portion of Nefazodone Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × 100
| rU | = | = peak area of the corresponding nefazodone related compound from the Sample solution |
| rS | = | = peak area of the corresponding nefazodone related compound from the Standard solution |
| CS | = | = concentration of the relevant USP RS in the Standard solution (mg/mL) |
| CU | = | = concentration of the Sample solution (mg/mL) |
[Note—Use the peak area for nefazodone hydrochloride in the Standard solution as rS to calculate any unknown impurity. ]
Acceptance criteria
Individual impurities:
See Impurity Table 1.
Total impurities:
NMT 0.5%
Impurity Table 1
| Name | Relative Retention Time |
Acceptance Criteria, NMT (%) |
|---|---|---|
| Nefazodone related compound A | 1.2 | 0.2 |
| Nefazodone related compound B | 0.94 | 0.2 |
| Nefazodone | 1.0 | — |
| Any other individual, unidentified impurity | — | 0.1 |
SPECIFIC TESTS
• Loss on Drying 731:
Dry a sample in a vacuum at 105
for 3 h: it loses NMT 0.5% of its weight.
731:
Dry a sample in a vacuum at 105 for 3 h: it loses NMT 0.5% of its weight.
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in tight containers. Store between 15 and 30.
and 30.
• USP Reference Standards 11
11
USP Nefazodone Hydrochloride RS 
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USP Nefazodone Related Compound A RS
1-(3-Chloropropyl)-4-(chlorophenyl)piperazine.
C13H18Cl2N2 273.20
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1-(3-Chloropropyl)-4-(chlorophenyl)piperazine.
C13H18Cl2N2 273.20
USP Nefazodone Related Compound B RS
2-(3-(4-(Chlorophenyl)-1-piperazinyl)propyl)-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one.
C25H32ClN5O2 470.01
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2-(3-(4-(Chlorophenyl)-1-piperazinyl)propyl)-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one.
C25H32ClN5O2 470.01
Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Hariram Ramanathan, M.S.
Associate Scientific Liaison 1-301-816-8313 |
(SM42010) Monographs - Small Molecules 4 |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 4007
Pharmacopeial Forum: Volume No. 35(3) Page 540